EP0303677A1 - Derives d'arylcyclobutyle pour le traitement de la maladie de parkinson - Google Patents

Derives d'arylcyclobutyle pour le traitement de la maladie de parkinson

Info

Publication number
EP0303677A1
EP0303677A1 EP88902510A EP88902510A EP0303677A1 EP 0303677 A1 EP0303677 A1 EP 0303677A1 EP 88902510 A EP88902510 A EP 88902510A EP 88902510 A EP88902510 A EP 88902510A EP 0303677 A1 EP0303677 A1 EP 0303677A1
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
dopamine
formula
compound
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP88902510A
Other languages
German (de)
English (en)
Inventor
John Andrew Rees
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boots Co PLC
Original Assignee
Boots Co PLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boots Co PLC filed Critical Boots Co PLC
Publication of EP0303677A1 publication Critical patent/EP0303677A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • Arylcyclobutyl derivatives for treatment of Parkinson's disease are arylcyclobutyl derivatives for treatment of Parkinson's disease.
  • This invention relates to the medical treatment of Parkinson's disease which is due to degenerative changes in the ganglia at the base of the cerebrum.
  • Ar is optionally substituted phenyl, R, is an optionally substituted aliphatic group or a carbocyclic or heterocyclic group and R 2 and R ⁇ are H or optionally substituted alkyl groups or R ? and R together with the nitrogen atom to which they are attached complete a heterocyclic ring
  • the compound of formula I is administered in conjunction with a pharmaceutically acceptable diluent or carrier.
  • the compound of formula I may be administered with a dopamine precursor such as levodopa and/or a dopa decarboxylase inhibitor such as carbidopa or benserazide
  • a particularly preferred compound of formula I is ,N-dimethyl-l-[1-(4-chloro- phenyl)cyclobutyl]-3-methylbutylamine hydrochloride monohydrate which is described in European Patent Application 230742.
  • N,N-Dimethyl-1-[1-(4-chloro- phenyl)cyclobutyl]-3-methylbutylamine hydrochloride monohydrate is an inhibitor of dopamine reuptake and when administered to humans gives an increase in dopamine levels in plasma. It may be used alone in the treatment of Parkinson's disease or may be used in combination with a dopamine precursor such as levodopa and/or a dopa decarboxylase inhibitor such as carbidopa or benserazide.
  • Compounds of formula I may be administered in any of the known pharmaceutical dosage forms for example solid dosage forms such as tablets or capsules or liquid dosage forms for example those forms intended for oral or parenteral administration.
  • the amount of the compound of formula I to be administered will depend on a number of factors including the age of the patient, the severity of the condition and the past medical history of the patient and always lies within the sound discretion of the administering physician but it is generally envisaged that the dosage of the compound of formula I to be administered will be in the range 1 to 1000 mg preferably 5 to 500 mg per day given in one or more doses.
  • the amount of levodopa given will be progressively increased by the physician until an optimum response is obtained.
  • the actual amount will be under the control of the physician and may be up to 8 g per day given in divided doses.
  • the amount of carbidopa given will be up to 100 mg per day.
  • the amount of benserazide given will be up to 200 mg per day.
  • the striata were homogenised with six strokes of a ptfe pestle having a clearance of 0.35 mm (manufactured by TRI-R Homogenisers Ltd.). The homogenate was centrifuged at 1000 x g for 10 minutes at 4°C and the supernatant containing a suspension of synaptosomes was used in the dopamine uptake inhibition tests described below.
  • Polythene specimen tubes containing 1.5 ml Krebs solution, 0.2 ml of a solution of N,N-dimethyl-l-[l-(4-chlorophenyl)cyclobutyl]-3- methylbutylamine hydrochloride monohydrate or distilled water as control, and 0.1 ml of the synaptosome suspension were provided with an atmosphere of 5% carbon dioxide and 95% oxygen and pre-incubated at 37°C for 5 minutes.
  • a solution of C-dopamine hydrochloride (Amersham International) was added (0.2 ml) to give a final concentration of 0.17 ⁇ M.
  • An in vivo test for dopamine reuptake inhibition relies on the fact that such reuptake inhibitors can prevent the entry of dopamine-depleting agents into neurons.
  • Depleting agents interfere with the neuronal storage mechanism for dopamine so dopamine leaks into the cytoplasm where it is metabolised by monoamine oxidase. Depleting agents therefore induce a large reduction in brain dopamine levels which can be measured experimentally.
  • Prior treatment with a dopamine reuptake inhibitor reduces the depletion of dopamine levels caused by subsequent administration of a depleting agent such as ⁇ -methyl-m-tyrosine.
  • mice Male Sprague-Dawley rats (180-220 g; Charles River) were randomly assigned to various treatment groups. Two groups were dosed orally with vehicle (distilled water) and the remaining groups were given oral doses of ,N-dimethyl-l-[1-(4-chlorophenyl)cyclo- butyl]-3-methylbutylamine hydrochloride monohydrate at 3 different doses. Thirty minutes later, one vehicle treated group and all the test groups were given an i.p. injection (2 ml/kg) of the depleting agent ⁇ -methyl-m-tyrosine (25 mg/kgj Sigma Chemical Co.). The group receiving vehicle (p.o.) plus ⁇ -methyl-m- tyrosine (i.p.) served as the depleted control. The remaining vehicle treated group was injected with saline i.p. to act as the absolute control.
  • HPLC high pressure liquid chromatography
  • the percentage prevention (P) of depletion of brain dopamine levels by test compounds is calculated from the formula
  • Control - Test compound/depletor P 100 x
  • the ED for ,N-dimethyl-l-[1-(4-chlorophenyl)cyclo-butyl]- 3-methylbutylamine hydrochloride monohydrate was calculated as 44 mg/kg (p.o.).
  • mice Male CD rats (Sprague-Dawley 350-400g; Charles River) were given 10, 30 or 100 mg/kg of , -dimethyl- 1-[l-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride monohydrate which was dissolved in distilled water and administered orally at a rate of 5 ml/kg. Control rats were orally administered distilled water. After one hour the rats were killed by C0 2 inhalation overdose, the chest cavity opened and blood immediately removed from the heart and mixed with an anticoagulant solution.
  • the rat blood/anticoagulant mixture was spun at 5750 x g for 20 minutes in a Heraeus Christ minicentrifuge at room temperature. The plasma was removed and kept at room temperature for as short a time as possible before analysis in the radiolabelled dopamine uptake assay.
  • the fresh plasma samples from the rat study were initially maintained at 37°C for 10-15 minutes before starting the assay. 300 ⁇ l of each plasma sample was added to six 5 ml polypropylene tubes already containing 50 ⁇ l of saline at room temperature. Four of these tubes were incubated at 37°C to assess active radiolabelled dopamine uptake. The other two tubes were immediately cooled to c.3°C and maintained at this temperature to account for passive radiolabelled dopamine uptake.
  • Millipore 1225 manifold linked to an Edwards 2-stage vacuum t pump The tubes were rinsed with 2 x 4 ml of ice-cold saline and this was also rapidly filtered. Finally, each manifold well was washed with 4 ml of ice-cold saline.
  • Venous blood (100 ml) was collected immediately before an oral 50 mg dose of N,N-dimethyl-1-[1- (4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride monohydrate was administered to six healthy human volunteers and a further venous blood sample was taken 3 hours later.
  • the plasma was separated by centrifugation at 2900 x g for 20 minutes at room temperature in a Heraeus Christ minicentrifuge and was stored at -20°C prior to analysis. The samples were thawed in a water bath at 37°C for 10-15 minutes prior to commencement of the in vitro dopamine uptake assay which was performed as described in (3) above except C-dopamine was used.
  • the assay was performed twice on plasma from each volunteer. The results obtained are given below:
  • the two tracts of the nigrostriatal dopamine system are independent and are located on either side of the , midline of the brain.
  • 6-hydroxy- dopamine 6-hydroxy- dopamine
  • rats will display characteristic circling behaviour after injection of dopaminergic drugs.
  • the direction of rotation is dependent on the stimulus employed.
  • Drugs which inhibit dopamine reuptake can only function on the unlesioned side of the brain and induce circling towards the lesion site (known as ipsilateral circling.)
  • Control values were determined for all rats by observing their spontaneous circling behaviour in the arenas without prior dosing. The mean turns per minute was always less than 1.
  • the rats were challenged with an intraperitoneal dose of methamphetamine (2 mg/kg) and immediately placed in the arenas. In these experiments circling behaviour was monitored during two period's, 0-lh and
  • Rats giving a mean of more than 5 ipsilateral turns per minute during the first hour in response to methamphetamine were used in subsequent tests. Following selection, the rats were used in groups of 5 or more rats to test the drug under investigation. The groups were made up of rats exhibiting varying responses to methamphetamine (always >5 turns/min as stated above) , the mean response of the group was always more than 10 ipsilateral turns per minute.
  • N,N-Dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3- methylbutylamine hydrochloride monohydrate was administered at 30 mg/kg orally and the amount of circling observed at various time periods after dosing is set out below: time (hrs) ipsilateral turns/min
  • Inhibition of dopamine reuptake in the brain reduces the rate at which dopamine is synthesised and metabolised (the turnover rate) . This can be assessed by measuring the amount of the dopamine metabolite DOPAC (dihydroxyphenylacetic acid) which accumulates in the brains of rats and mice.
  • DOPAC dopamine metabolite
  • the administration of probenecid blocks active transport of DOPAC out of the brain. The subsequent rise in brain DOPAC concentrations is attenuated by drugs which inhibit dopamine reuptake.
  • N,N-Dimethyl-1-[l-(4-chlorophenyl)cyclobutyl]-3- methylbutylamine hydrochloride monohydrate (10 mg/kg) was administered orally to male Sprague-Dawley rats (180-250g) or male CD! mice (25-30g) (Charles River). One group of animals was killed two hours later. An additional group was administered probenecid (200 mg/kg i.p.; Sigma Chemical Co.) 30 minutes after the drug and then killed after a further 90 minutes. The animals were killed by decapitation and brains were rapidly removed and dissected on an ice-chilled porcelain plate.
  • samples were then centrifuged at 30,000 x g (whole brain samples) or at 3,500 x g (striata) using a microfuge (Beckman) set up to take 1200 ⁇ l polypropylene tubes. Aliquots (50 ⁇ l) of the clear supernatants were then injected automatically into the chromatographic system for the separation and quantification of DOPAC.
  • High pressure liquid chromatography HPLC combined with electrochemical detection (ECD) was employed to assay DOPAC.
  • a mobile phase 0.1M Na 2 HP0, ⁇ CH ⁇ 0H (84:16%) containing 0.1% octanesulphonic acid, 0.1% EDTA and 0.01% Na 2 S 2 0
  • Dupont 870 pump module at a flow-rate of 1.0 ml/ in to a reverse-phase analytical column (25 x 0.4 cm) and guard column (both packed with 5 ⁇ m Spherisorb ODS 2) maintained at 45°C in a thermostatically .controlled cabinet.
  • Experiments marked A show the ability of drug alone to reduce brain DOPAC concentrations.
  • Experiments marked B show the ability of the drug to attenuate the probenecid-induced elevation of brain DOPAC concentrations.
  • the decreases in brain DOPAC concentrations are indicative of dopamine reuptake inhibition causing a decrease in dopamine turnover in drug treated animals.
  • N,N-dimethyl-l-[1-(4-chloro- phenyl)cyclobutyl]-3-methylbutylamine hydrochloride monohydrate was illustrated by the following trial.
  • the amount of dopamine in the plasma of six humans subjects who had received a single dose of 30 mg N,N-dimethyl-1-[l-(4-chlorophenyl)cyclobutyl]-3- methylbutylamine hydrochloride monohydrate per day for seven days was • measured in plasma samples taken two hours after administration.
  • the mean value of domamine in picograms/ml is set out below at days 1, 4 and 7.
  • Eight human subjects who were given placebo tablets provides plasma samples from which the mean control dopamine levels given below were obtained.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Materials For Medical Uses (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Les composés décrits sont représentés par la formule (I), où Ar représente un phényle éventuellement substitué, R1 représente un groupe aliphatique éventuellement substitué et R2 et R3 représentent H ou des groupes alkyles éventuellement substitués ou R2 et R3 complètent, avec l'atome d'azote auquel ils sont liés, un anneau hétérocyclique. Lesdits composés sont utilisés dans le traitement de la maladie de Parkinson. Les composés de la formule (I) peuvent être administrés avec un précurseur de dopamine, tel que la lévodopa, et/ou avec un inhibiteur de décarboxylase de dopa, tel que la carbidopa ou un bensérazide. Un composé préféré de la formule (I) est constitué par un monohydrate d'hydrochlorure de N,N-diméthyl-1-[1-(4-chlorophényl)-cyclobutyl]-3-méthylbutylamine.
EP88902510A 1987-02-28 1988-02-25 Derives d'arylcyclobutyle pour le traitement de la maladie de parkinson Pending EP0303677A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB878704777A GB8704777D0 (en) 1987-02-28 1987-02-28 Medical treatment
GB8704777 1987-02-28

Publications (1)

Publication Number Publication Date
EP0303677A1 true EP0303677A1 (fr) 1989-02-22

Family

ID=10613147

Family Applications (2)

Application Number Title Priority Date Filing Date
EP88301625A Expired - Lifetime EP0282206B1 (fr) 1987-02-28 1988-02-25 Dérivé-arylcyclobutylalkylaminique pour le traitement de la maladie de Parkinson
EP88902510A Pending EP0303677A1 (fr) 1987-02-28 1988-02-25 Derives d'arylcyclobutyle pour le traitement de la maladie de parkinson

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP88301625A Expired - Lifetime EP0282206B1 (fr) 1987-02-28 1988-02-25 Dérivé-arylcyclobutylalkylaminique pour le traitement de la maladie de Parkinson

Country Status (9)

Country Link
US (2) US4816488A (fr)
EP (2) EP0282206B1 (fr)
JP (1) JPH0643299B2 (fr)
AT (1) ATE58059T1 (fr)
DE (1) DE3860960D1 (fr)
GB (1) GB8704777D0 (fr)
GR (1) GR3001395T3 (fr)
WO (1) WO1988006444A1 (fr)
ZA (1) ZA881417B (fr)

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GB8501192D0 (en) * 1985-01-17 1985-02-20 Boots Co Plc Therapeutic agents
GB8531071D0 (en) * 1985-12-17 1986-01-29 Boots Co Plc Therapeutic compound
JP2675573B2 (ja) * 1988-03-31 1997-11-12 科研製薬株式会社 脳機能改善剤
IE61928B1 (en) * 1988-11-29 1994-11-30 Boots Co Plc Treatment of obesity
GB9309749D0 (en) * 1993-05-12 1993-06-23 Boots Co Plc Therapeutic agents
US5459164A (en) * 1994-02-03 1995-10-17 Boots Pharmaceuticals, Inc. Medical treatment
DE19518988A1 (de) * 1995-05-29 1996-12-05 Basf Ag Verwendung arylsubstituierter Cyclobutylalkylamine zur Behandlung der Fettleibigkeit
GB9619757D0 (en) 1996-09-21 1996-11-06 Knoll Ag Chemical process
GB9619962D0 (en) * 1996-09-25 1996-11-13 Knoll Ag Medical treatment
GB9619961D0 (en) * 1996-09-25 1996-11-13 Knoll Ag Medical treatment
GB9727131D0 (en) 1997-12-24 1998-02-25 Knoll Ag Therapeutic agents
US6476078B2 (en) * 1999-08-11 2002-11-05 Sepracor, Inc. Methods of using sibutramine metabolites in combination with a phosphodiesterase inhibitor to treat sexual dysfunction
US6974838B2 (en) * 1998-08-24 2005-12-13 Sepracor Inc. Methods of treating or preventing pain using sibutramine metabolites
US6331571B1 (en) * 1998-08-24 2001-12-18 Sepracor, Inc. Methods of treating and preventing attention deficit disorders
AU2007200334B8 (en) * 1998-08-24 2010-10-21 Sepracor, Inc. Methods of using and compositions comprising dopamine reuptake inhibitors
US6339106B1 (en) 1999-08-11 2002-01-15 Sepracor, Inc. Methods and compositions for the treatment and prevention of sexual dysfunction
US6696495B2 (en) 1998-12-02 2004-02-24 Snowden Pharmaceuticals, Llc Treatment of disorders secondary to organic impairments
US6323242B1 (en) 1998-12-02 2001-11-27 Peter Sterling Mueller Treatment of disorders secondary to organic impairments
BG65170B1 (bg) * 1999-03-17 2007-05-31 Knoll Gmbh Използване на n-заместени производни на 1-[1-(4-хлорофенил)циклобутил]-3-метилбутиламин за производство на лекарство за лечение на разстройства при храненето
US6803387B1 (en) 1999-03-19 2004-10-12 Abbott Gmbh & Co. Kg Treatment of neuropathic pain or fibromyalgia
US6441046B1 (en) 1999-03-19 2002-08-27 Abbott Gmbh & Co. Kg Control of metabolism
US6376554B1 (en) 1999-03-19 2002-04-23 Knoll Pharmaceutical Company Method of treating sexual dysfunction
US6376551B1 (en) 1999-03-19 2002-04-23 Knoll Pharmaceutical Company Treatment of chronic fatigue syndrome
AU3760600A (en) 1999-03-19 2000-10-09 Knoll Pharmaceutical Company Treatment of orthostatic hypotension
AU3899100A (en) 1999-03-19 2000-10-09 Knoll Pharmaceutical Company Treatment of hyperactivity disorders
WO2000056308A1 (fr) 1999-03-19 2000-09-28 Knoll Pharmaceutical Company Prevention de maladies cardio-vasculaires
JP2002539250A (ja) 1999-03-19 2002-11-19 クノール・ゲー・エム・ベー・ハー 肺高血圧症の治療
US6552087B1 (en) 1999-03-19 2003-04-22 Abbott Gmbh & Co. Kg Therapeutic agent comprising (+)-sibutramine
GB9915617D0 (en) 1999-07-05 1999-09-01 Knoll Ag Therapeutic agents
US6399826B1 (en) 1999-08-11 2002-06-04 Sepracor Inc. Salts of sibutramine metabolites, methods of making sibutramine metabolites and intermediates useful in the same, and methods of treating pain
US6610887B2 (en) 2001-04-13 2003-08-26 Sepracor Inc. Methods of preparing didesmethylsibutramine and other sibutramine derivatives
EP1567180A4 (fr) * 2002-06-04 2010-03-10 Avicena Group Inc Methodes de traitement de dysfonctionnements cognitifs par modulation du metabolisme energetique du cerveau
CN101098850B (zh) 2005-01-06 2010-09-15 Cj第一制糖株式会社 ***的无机酸盐

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IE52768B1 (en) * 1981-04-06 1988-02-17 Boots Co Ltd 1-arylcyclobutylalkylamine compounds useful as therapeutic agents
IE56001B1 (en) * 1982-09-30 1991-03-13 Boots Co Plc 1-arylcyclobutylmethylamine compounds
IE56000B1 (en) * 1982-09-30 1991-03-13 Boots Co Plc 1-arylcyclobutylalkylamine compounds
GB8501192D0 (en) * 1985-01-17 1985-02-20 Boots Co Plc Therapeutic agents
GB8531071D0 (en) * 1985-12-17 1986-01-29 Boots Co Plc Therapeutic compound

Non-Patent Citations (1)

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Also Published As

Publication number Publication date
EP0282206A1 (fr) 1988-09-14
ZA881417B (en) 1988-09-02
US4816488A (en) 1989-03-28
JPH01500356A (ja) 1989-02-09
EP0282206B1 (fr) 1990-11-07
US4871774A (en) 1989-10-03
GR3001395T3 (en) 1992-09-11
JPH0643299B2 (ja) 1994-06-08
GB8704777D0 (en) 1987-04-01
DE3860960D1 (de) 1990-12-13
ATE58059T1 (de) 1990-11-15
WO1988006444A1 (fr) 1988-09-07

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